Adverse effects and countermeasures

Like with most medication, the therapeutic use of cannabis or cannabinoids can elicit adverse effects such as tachycardia, dry mouth, blurred vision, vertigo, low blood pressure, panic attack, red eyes or itchy skin.

Similar to its therapeutic effects, the adverse effects related to cannabis use are mostly due to THC and its effect on the CB1 receptor.

Although these effects are generally innocuous and transient, they can be upsetting for uninformed or inexperienced patients.

Here we discuss known adverse effects of cannabis / THC intoxication and, where possible, which countermeasures can be taken.

Although cannabinoids can exert very strong physical and psychological effects, they are actually quite mild from a toxicological point of view. cannabinoids can be cytotoxic to certain types of cancer cells (for instance see: Gustafsson et al., 2009; Powles et al., 2005) but not under normal physiological conditions.

Similarly, cannabinoids have little or no mutagenic potential under normal conditions and are therefore unlikely to cause cancer for instance.

This results in an unusually high Margin Of Exposure/MOE: the ratio of the lowest dose required for the desired (therapeutic) effect and the dose that elicits adverse or potentially lethal effects. Many therapeutic drugs, but also recreational drugs such as alcohol or nicotine have MOEs <10, meaning that it is relatively easy to overdose. Opiates, cocaine, amphetamines, ecstasy and benzodiazepines typically have MOEs >100. Cannabis on the other hand has an MOE >10.000 making it a very safe drug (Lachenmeier and Rehm, 2015).

Please note that although cannabis and cannabinoids are relatively innocuous in themselves, smoking cannabis, like tobacco produces compounds that are cytotoxic and mutagenic (Moir et al., 2008). This is relevant as the majority of therapeutic users prefers smoked/inhaled cannabis (Sexton et al., 2016).

Acute physical effects

· Tachycardia: The most common side effect of cannabis (read THC) consumption is tachycardia. This is transient and dose-related and usually innocuous in healthy young users. However, patients, especially those with a heart condition, should be cautious and contact a physician when in doubt.

· Dry mouth: Cannabis consumption can lead to a dry mouth. This is due to activation of CB1 and CB2 receptors in the submandibular gland (Prestifilippo et al., 2006) and is generally considered innocuous.

· Blurred vision: Cannabis consumption can lead to blurred vision. This is probably a result of THC lowering intra-ocular pressure (which is the basis of the therapeutic use of cannabis against glaucoma). Blurred vision of cannabis use is transient en in itself innocuous.

· Nausea/dizziness: Nausea and dizziness are among the most reported side effects of cannabis (read THC) consumption. The effects are dose-dependent, transient and generally innocuous.

· Itchy skin: Although cannabis is often used to treat itchy skin or similar disorders, itchy skin can also be a side-effect of cannabis use. Itchy skin is transient and harmless.

· Hunger / low blood sugar: Cannabis use is associated with lowered blood sugar levels (Penner et al., 2013) and increased appetite. For this reason cannabis is used to treat Diabetes and anorexia-like symptoms but it can also be experienced and adverse effect. Cannabis-induced low blood sugar is transient and generally harmless.

· Hypothermia: THC in cannabis can produce hypothermia via the CB1 receptor. This effect is transient and generally harmless. Please note that while CBD can revert several effects of THC, it tends to exacerbate THC-induced hypothermia (Taffe et al., 2015)

· Reduced motor control: THC in cannabis can reduce motor control and locomotion. This effect is transient and generally harmless. Please note that while CBD can revert several effects of THC, it tends to exacerbate THC-induced hypolocomotion (Taffe et al., 2015).

Acute psychological effects

· Short-term memory loss: One of the most notable side effects of cannabis use is short-term memory loss. Although this is beneficial for instance for the treatment of posttraumatic stress disorders or for generalized stress relief, it can also be experienced as an adverse effect. Memory loss is induced via THC and CB1 and is transient and innocuous.

· Loss of concentration: As a direct consequence of reduced short-term memory function, cannabis use can also lead to loss of focus or concentration. These effects are mediated via THC and CB1 and are transient in nature.

· Panic attack/paranoia: Although cannabis can be used to treat Anxiety or stress, its use can also elicit a panic attack or paranoia. These panic attacks are likely a result of the acute effects mentioned above and are mediated by THC. Cannabis-induced Anxiety or paranoia is transient and in itself harmless.

Countermeasures

Acute adverse effects of cannabis are transient and are usually easily counteracted with activity, controlled breathing and sugar.

As most adverse effects directly or indirectly result from low blood pressure or low blood sugar, light activity such as walking and consuming sugary food or drinks are often sufficient to abolish these adverse effects in minutes.

Similarly, deep belly breathing can often revert adverse effects such as panic or Anxiety in seconds or minutes.

In addition, many effects of THC can be counteracted by CBD although it should be noted that CBD can paradoxically increase the effects of THC by inhibiting its degradation via inhibition of Cytochrome P450 enzymes.

Long-term effects and contraindications

· Carcinogenesis: cannabinoids themselves are not carcinogenic or mutagenic. However, smoking is a popular route of Cannabinoid administration and smoking cannabis, like smoking tobacco produces carcinogenic compounds. Interestingly, compared to smoking tobacco, long-term smoking of cannabis actually reduces the risk of cancer in squamous cells lining the respiratory tract in head and neck by approximately 50% (Liang et al., 2009). Vaping or ingesting cannabinoids is likely to greatly reduce the risk of carcinogenesis.

· Respiratory tract: cannabinoids themselves do not negatively influence the respiratory tract. However, smoking is a popular route of Cannabinoid administration and smoking cannabis, like smoking tobacco produces pathogenic/carcinogenic compounds. In addition, cannabis smoke tends to be inhaled longer and deeper, resulting in increased tar and carbon monoxide levels compared to smoking tobacco. As a result, biopsies from chronic cannabis smokers often show histopathological changes such as basal cell hyperplasia, stratification, goblet cell hyperplasia, inflammation, basement membrane thickening and squamous cell metaplasia. Vaping or ingesting cannabis is likely to greatly reduce the risk of respiratory tract disease.

· Immune system: The endocannabinoid system is prominently involved in immune regulation. As a consequence, cannabinoids have great regulatory potential in the immune system. Tight regulation of the immune system is crucial to healthy life: an overactive immune system can evoke auto-immune disorders whereas a weak immune system leaves the body prone to infection. THC appears to be mainly anti-inflammatory at low nanomolar concentrations but pro-inflammatory at low micromolar concentrations (Berdyshev et al., 1997). Cannabis use is mostly associated with immunosuppression/anti-inflammatory action, similar to most anti-inflammatory drugs. It is important to realize that chronic cannabis use therefore roughly equates to chronic immunosuppression, which in turn could negatively impact general health.

· Reproductive system:

o Behavior: Cannabis use can influence many types of behavior, including sexual behavior in a dose-dependent way. Both men and women tend to respond positively to occasional low or moderate doses of cannabis with increased sensitivity to touch, increased desire and increased sexual activity. Higher doses or frequency of use can have the opposite effect and inhibit sexual motivation or erectile function for instance.

o Male reproduction: The endocannabinoid system is not just present in the brain (affecting behavior) but in most tissues including reproductive tissues and it can thus influence many aspects of reproductive physiology. An in vitro study showed that THC dose-dependently reduces sperm motility and inhibits the acrosome reaction (Whan et al., 2006). It should be noted though that THC primarily affects motility in ‘poor swimming sperm’. Motility in ‘fast swimming sperm’ is only affected by very high THC concentrations (4.8 μM or ±1500 μg/l plasma), which are not likely to reached after therapeutic or even heavy recreational use of cannabis. Still, cannabis/THC can negatively influence fertility, especially in males that are on the border of infertility.

o Female reproduction: Animal and in vitro studies have shown that cannabis/THC can negatively affect ovulation and successful pregnancy (Kostellow et al., 1980; Yao et al., 2018) but only at very high concentrations, unlikely to be attained in humans. In fact, a systematic review in humans failed to find a negative impact of cannabis use during pregnancy on fetal or child development (Zhang et al., 2017).

· Cardiovascular system: As discussed above, tachycardia and peripheral vasodilation are consistent acute side effects of cannabis use. In healthy young people this is harmless but in elderly people, medical cannabis users or patients with cardiovascular problems this could be relevant. To put things in perspective, smoking cannabis elevates the risk of myocardial infection at population level, but less so then eating a heavy meal. At the individual level, smoking cannabis elevates the risk of heart attack less than exposure to traffic, alcohol, coffee, air pollution, negative emotions, anger, a heavy meal, positive emotions, sex or cocaine use (Nawrot et al., 2011).

· Gastrointestinal system: One adverse effect that is occasionally observed with chronic heavy cannabis use is ‘cannabis hyperemesis syndrome’. Until recently the only remedy was abstinence from cannabis use and taking hot showers. In line with the latter observation, the TRPV1 receptor is now implicated in cannabis hyperemesis syndrome and treatment with topical capsaicin (TRPV1 agonist) appears effective (Dezieck et al., 2017; Moon et al., 2018). Other reported treatments for hyperemesis syndrome are haloperidol (often used as anti-psychotic and anti-emetic) and propranolol (often used against high blood pressure and Anxiety) (Jones and Abernathy, 2016; Richards and Dutczak, 2017).

· Central nervous system

o Cognition: Short-term memory loss is a well-known acute effect of cannabis use. Whether chronic cannabis use has a long-term effect on cognition remains controversial and requires more research.

o Motor control: Although cannabis use acutely and negatively affects motor control there is no indication that cannabis can negatively affect motor control on a longer term.

o Mental disorders: Several mental disorders such as depression, Anxiety, bipolar disorder, Psychosis and schizophrenia have been associated with cannabis use but a causal link was never shown. In fact, several mental disorders are now linked to mutations in the genes underlying the endocannabinoid system / ECS variation, suggesting cannabinoids may be used to treat these very disorders. Regardless, caution is advised for the use of cannabinoids in patients with a history of mental disease.

· Addiction: Like other psychoactive drugs, cannabis (read THC) has the potential to develop psychological dependence and to a degree physical dependence. Whether cannabis or Cannabinoid use leads to dependence relies on several factors:

o Genetic passport: every individual has a unique genetic passport, which determines which diseases we are likely to get. Many diseases are now beginning to be recognized as ECS deficiencies, suggesting these can be treated with Cannabinoid supplements. Abstinence from cannabinoids is likely to affect people with an ECS deficiency harder than people with a fully functional ECS.

o Route of application: Addiction or dependence is mostly attributed to the smoking of cannabis, especially when mixed with tobacco. Oral or sublingual application of cannabinoids is far less likely to cause dependence. Routes of application that do not cause psychoactive effects (for instance topical application to the skin) are not considered addictive.

o Psychoactivity of cannabinoids: Cannabis / THC is considered addictive mostly because of its psychoactive properties. cannabinoids such as CBD are not psychoactive and are considered to have no abuse potential. In fact, CBD can be used to suppress or counteract the addictive potential of cannabis / THC (Crippa et al., 2013), alcohol (Viudez-Martínez et al., 2017) or tobacco (Morgan et al., 2013).

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